Background: Some smokeless tobacco products (SLT) have been shown to be associated with only a fraction of the risks of cigarettes. This study assessed South African smokers’ interest in switching to a hypothetical reduced harm SLT product. Methods: The 2007 South African Social Attitudes Survey was analysed for 678 exclusive cigarette smokers. Respondents were asked about their perceptions about relative harm of snuff compared to cigarettes, and their interest in switching to snuff if informed it was 99% less harmful than cigarettes. Results: About 49.7% of exclusive cigarette smokers believed that snuff was equally as harmful as cigarettes; 12.9% thought snuff was more harmful; 5.7% thought snuff was less harmful; while 31.8% did not know if there was a difference in harm between snuff and cigarettes. Approximately 24.2% of exclusive cigarette smokers indicated interest in switching to snuff, with significantly greater interest observed among those exposed to 100% smoke-free work environment. Interest in switching was highest (34.7%) among smokers who believed a priori that using snuff was more harmful than cigarettes, and lowest (14.5%) among those who did not know if there was a difference in harm. In a multi-variable adjusted logistic regression model, this latter group remained less likely to be interested in harm reduction switching (adjusted odds ratio = 0.42; 95% CI: 0.19–0.91). Conclusion: About a quarter of smokers indicated interest in harm reduction switching to snuff. SLT products have a potential role in reducing the harm from smoking in South Africa, but only if they are not used to circumvent smoke-free laws that have been associated with reduced smoking.